Phosphoproteomic Profiling Identifies Focal Adhesion Kinase as a Mediator of Docetaxel Resistance in Castrate Resistant Prostate Cancer
Menée in vitro, cette étude suggère l'intérêt d'une stratégie basée sur l'inhibition de la kinase d'adhérence focale pour surmonter une résistance au docétaxel dans le traitement des patients atteints d'un cancer de la prostate résistant à la castration
Docetaxel remains the standard-of-care for men diagnosed with metastatic castrate resistant prostate cancer (CRPC). However, only ~50% of patients benefit from treatment and all develop Docetaxel-resistant disease. Here, we characterize global perturbations in tyrosine kinase signaling associated with Docetaxel-resistance and thereby develop a potential therapeutic strategy to reverse this phenotype. Using quantitative mass spectrometry-based phosphoproteomics, we identified that metastatic Docetaxel-resistant prostate cancer cell lines (DU145-Rx and PC3-Rx) exhibit increased phosphorylation of focal adhesion kinase (FAK) on Y397 and Y576, in comparison to parental controls (DU145 and PC3, respectively). Bioinformatic analyses identified perturbations in pathways regulating focal adhesions and the actin cytoskeleton and in protein-protein interaction networks related to these pathways in Docetaxel-resistant cells. Treatment with the FAK tyrosine kinase inhibitor (TKI) PF-00562271 reduced FAK phosphorylation in the resistant cells, but did not affect cell viability or Akt phosphorylation. Docetaxel administration reduced FAK and Akt phosphorylation, while co-treatment with PF-00562271 and Docetaxel resulted in an additive attenuation of FAK and Akt phosphorylation and overcame the chemoresistant phenotype. The enhanced efficacy of co-treatment was due to increased autophagic cell death, rather than apoptosis. These data strongly support that enhanced FAK activation mediates chemoresistance in CRPC, and identify a potential clinical niche for FAK TKIs, where co-administration with Docetaxel may be used in CRPC patients to overcome chemoresistance.
http://mct.aacrjournals.org/content/early/2013/11/05/1535-7163.MCT-13-0225-T.abstract